The invention relates generally to a device and method for monitoring and controlling the iontophoretic transport of a compound through a localized region of an individual""s body tissue. In particular, the invention employs a novel reference electrode, in conjunction with at least one of two iontophoretic electrodes, to monitor and control the electrical resistance of the tissue at the localized region. The invention is particularly useful when there is a need to precisely control the administration of a compound to, or the extraction of a compound from a body tissue, such as in the administration or monitoring of a therapeutic drug or glucose, for example.
Iontophoresis involves the transport of a compound across a body tissue under the influence of an electrical current. In practice, two iontophoretic electrodes are placed on a body tissue, typically the skin or mucosa, in order to complete a circuit. At least one of the electrodes is considered to be an active iontophoretic electrode, while the other may be considered as a return, inactive, or indifferent electrode. Compound transport across the tissue occurs when a current is applied to the electrodes through the tissue. Compound transport may occur as a result of a direct electrical field effect (e.g., electrophoresis), an indirect electrical field effect (e.g., electroosmosis), electrically induced pore formation (electroporation), or a combination of any of the foregoing.
Iontophoretic techniques have been used to deliver compounds to, or extract compounds from, body tissues of a patient. When iontophoresis is used to deliver a compound to the tissue, an active iontophoretic electrode is provided with a reservoir containing the compound to be delivered, as well as optional additional compounds that may serve to enhance iontophoretic delivery. For example, U.S. Pat. No. 6,248,349 to Suzuki et al. describes an iontophoretic electrode in combination with an interface capable of making contact with the skin that effectively holds a drug and humectant mixture. The humectant is described as improving iontophoretic drug delivery by controlling the concentration of the drug at the delivery site. Similarly, when iontophoresis is used to extract a compound from the tissue, the active iontophoretic electrode may be provided with a reservoir for collecting the extracted compound. Further, additional compounds may be added to the receiving reservoir to enhance iontophoretic extraction. Once extracted, the compound may be analyzed using sensors, processors, and algorithms known in the art. See U.S. Pat. Nos. 6,139,1718; 6,144,869; 6,180,416; 6,201,979; 6,233,471; 6,284,126; and 6,326,160.
In some instances, the process of iontophoresis can cause irritation, sensitization, and pain at the application site. The effects of the electrical current on sensitization have been investigated in various attempts to develop iontophoretic methods that are capable of maintaining the electrical current and/or potential at a comfortable level. It has been found that the degree of irritation, sensitization, and/or pain is directly proportional to the applied current or voltage. Thus, there is a need to apply iontophoretic current at a level that is effective to transport compounds of interest at a desired rate but that does not cause tissue irritation, sensitization, and/or pain.
A majority of the known iontophoretic methods employ a constant direct current (DC) iontophoretic signal and suffer from a number of shortcomings as a consequence. It is generally believed that the constant driving force provided by the DC current will produce a constant, unwavering permeant flux. It has been observed, however, that a constant current DC signal does not result in constant flux. The constant DC causes the electrical resistance of the tissue to change as a result of variations in tissue porosity, pore surface charge density, and effective pore size over the course of treatment. As a result, the amount of compound transported across a tissue varies with time and cannot be controlled, monitored, or predicted effectively. The inability to control analyte flux during iontophoresis has proven to be a major constraint to the marketing and regulatory success of iontophoretic products.
In addition, iontophoretic techniques that employ a constant DC signal can result in the formation of unwanted byproducts. For example, the application of a constant direct current to a tissue can result in water hydrolysis at the treatment site, causing protons to accumulate at the anode and hydroxide ions to accumulate at the cathode. The resulting shift in pH at the electrodes may cause tissue irritation and/or damage. In extreme cases, this resulting electrolysis causes gas formation at the interface between the active electrode and tissue in contact with it. As a consequence, interfacial electrical resistance may be altered as well. The highly mobile hydrogen and hydroxide ion byproducts of water hydrolysis competes against the permeant for the electrical current, thereby decreasing permeant transport efficiencies.
As a whole, the overarching problem associated with DC iontophoretic systems is their high degree of variability. A number of attempts have been made to overcome the problems associated with constant DC signals by using pulsed DC signals and signals of different waveforms. In theory, pulsed DC signals improve iontophoretic delivery by allowing skin capacitance to discharge, thereby dissipating accumulative pore charging and the resulting formation of electropotential barriers. This capacitance discharge is thought to permit more controlled current flow and agent transport. In some instances, employing pulsed DC signals may involve switching the polarity of electrodes between the pulses. See U.S. Pat. No. 5,771,890 to Tamada. In practice, however, many DC pulsed methods suffer from at least some of the same general drawbacks as the constant current DC methods.
Iontophoretic methods that use alternating current (AC) signals, with or without a DC offset, have exhibited improved performance for both compound delivery and extraction. The premise of AC constant conductance iontophoresis is that molecular transport across a tissue is directly proportional to the tissue""s conductivity and inversely related to the tissue""s resistivity. The conductance of the membrane is a direct measure of the ease of passage of molecules and ions, but in particular, sodium and chloride ions. It has been found that, at constant current levels, the molecular transport though a membrane is related to the conductance of the membrane. AC iontophoretic methods are described in U.S. patent application Ser. No. 09/783,138, entitled xe2x80x9cMethods for Delivering Agents Using Alternating Current,xe2x80x9d filed on Feb. 13, 2001, corresponding to International Patent Publication No. WO 01/60449. AC iontophoretic methods are also described in U.S. patent application Ser. No. 09/783,696, entitled xe2x80x9cMethods for Extracting Substances Using Alternating Current,xe2x80x9d filed on Feb. 13, 2001, corresponding to International Patent Publication No. WO 01/60448.
In order to reduce the energy requirements needed to effect iontophoretic transport, it has been discovered that application of a barrier-modifying substance (also referred to herein as a xe2x80x9cbarrier-modifying agentxe2x80x9d or xe2x80x9cbarrier modifierxe2x80x9d) to the body tissue, either prior to or during AC iontophoresis, lowers the potential voltage difference needed to achieve electroporation. As discussed in U.S. patent application Ser. No. 10/014,741, entitled xe2x80x9cMethod of Increasing the Battery Life of an Alternating Current Iontophoresis Device Using a Barrier-Modifying Agent,xe2x80x9d filed on Dec. 10, 2001, the use of such barrier modifiers makes it possible to maintain the rate at which a compound of interest can be transported through a body tissue at lower electrical voltage levels. This reduction in applied voltage ultimately results in increased battery life, extended treatment duration, decreased treatment cost, and increased patient comfort.
In order to optimize iontophoretic methods, there is a need to monitor the amount of current being applied to the tissue of interest, as well as the transport of the specific compound through the tissue. A number of techniques have been developed to monitor iontophoretic current. For example, U.S. Pat. No. 5,246,418 to Haynes et al. discloses a method of reducing irritation during iontophoresis using a circuit that provides electrical communication between the iontophoretic electrodes. In essence, the circuit monitors and controls the current passing through the electrodes and the tissue. Similarly, U.S. Pat. No. 4,141,359 to Jacobsen et al. describes an epidermal iontophoresis device that includes an impedance-checking circuit coupled to the iontophoretic electrodes, and a safety-shutdown circuit coupled to the impedance-checking circuit that prevents an excessive voltage differential from being applied across the electrodes.
In previous methods for measuring electrical resistance associated with iontophoresis, it has been assumed that the resistance measured across the iontophoretic electrodes is evenly distributed across the two sites. For example, it was assumed that a measured resistance of 10 kxcexa9 across the electrodes of an iontophoretic system indicated that the resistance at each electrode was 5 kxcexa9. It has recently been discovered, however, that electrical resistance at the iontophoretic electrodes may change independently from each other during iontophoresis. In many cases, a constant measured resistance between two electrodes results from an increasing resistance at one electrode and a decreasing resistance at the other electrode. Thus, there is a need in the art to monitor the electrical resistance and control the electrical parameters at iontophoretic electrodes independently from each other in order to improve iontophoretic transport precision.
In a first embodiment, the invention relates to a device for iontophoretically transporting a compound through a localized region of an individual""s body tissue. The device includes first and second iontophoretic electrodes, a reference electrode, a current source, and a monitoring means. The first electrode is adapted to be placed in ion-conducting relation with the localized region to allow iontophoretic transport of a compound therethrough. The second and reference electrode are each adapted to contact the individual""s body tissue, and all electrodes are spaced apart from each other. Optionally, the second and/or the reference electrodes are adapted to be placed in ion-conducting relation with the body tissue as well. The current source is electrically connected to the first and second electrodes and is capable of applying an AC or DC current to the localized region of body tissue to effect iontophoretic transport of the compound through the localized region. The monitoring means monitors the electrical resistance of the localized region by measuring any voltage difference between the reference electrode and at least one of the first and second electrodes. To ensure accurate monitoring of the resistance of the localized region, the reference electrode is typically immobilized with respect to at least one of the first and second electrodes.
Preferably, the inventive device employs a controller. The controller may control the current or voltage applied to the localized region of body tissue by the current source. The controller may also control the duration of current and/or voltage application. Typically, the controller is adapted to control the current applied to the localized region according the electrical resistance of the localized region as monitored by the monitoring means. A feedback mechanism may be employed, wherein the controller is adapted to control the current applied to the localized region to maintain the electrical resistance of the localized region within a predetermined resistance range. Optimally, the controller maintains the resistance of the tissue in contact with the first electrode and the reference electrode at a constant value.
When the device is adapted to transport a compound into the localized region, the first electrode may be constructed as a component of an electrode assembly adapted to deliver the compound through the localized region. In such cases, the assembly may include a reservoir that houses the compound, e.g., a pharmacologically active agent. When the device is adapted to extract a compound from the localized region, the first electrode may be constructed as a component of an electrode assembly adapted to receive a compound transported through the localized region. In such cases, the assembly may house a reservoir for collecting and containing the extracted compound. In either case, the assembly may also include a barrier-modifying agent that may be delivered to the localized region. Typically, barrier-modifying agents are permeation enhancers.
Optionally, the inventive device may include a sensor in the reservoir for measuring the quantity and/or concentration of the compound to be delivered to, or extracted from, the localized region. The sensor may operate according to any known sensing technique. For example, the sensor may be an electrochemical sensor comprised of a working electrode, a counter electrode, and an optional sensor reference electrode. Typically, but not necessarily, the sensor reference electrode does not also serve as the reference electrode used in monitoring the electrical resistance of the localized region, as discussed above. The sensor, for example, may be a coulometric, amperometric, or potentiometric sensor. Similarly, the sensor may be an optical sensor.
The monitoring means may be adapted to continuously or intermittently monitor the electrical resistance of the localized region. Ordinarily, intermittent monitoring involves monitoring at a predetermined regular interval occurring at a constant frequency. However, the predetermined intervals may occur at an increasing or decreasing frequency as well. In some instances, the monitoring means is adapted to monitor the electrical resistance of the localized region at intervals selected according to the electrical potential applied by an iontophoretic power supply that serves as the current source.
In another embodiment, the invention relates to a method for iontophoretically transporting a compound through a localized region of an individual""s body tissue. The method involves placing a first electrode in ion-conducting relation with the localized region and placing second and reference electrodes in contact with the individual""s body tissue. Once the electrodes are in appropriate positions, i.e., placed apart from each other, a current is applied to the localized region of body tissue through the first and second electrodes to effect iontophoretic transport of a compound through the localized region. While the current is applied, the electrical resistance of the localized region is monitored. This method can be carried out by measuring any voltage difference between the reference electrode and at least one of the first and second electrodes.
Optionally, the inventive method is carried out using the inventive device. While the invention may be used to effect iontophoretic compound transport across any type of tissue, the inventive method is particularly suited for iontophoretic compound transport across skin, mucosa, or eye tissue.
Thus, the invention improves previous known methods for iontophoretically transporting a compound through a localized region of an individual""s body tissue wherein a current is applied to the localized region of body tissue through first and second electrodes that are each in contact with the body tissue. The improvement involves measuring the tissue resistance at the first electrode independently from any measurement of tissue resistance at the second electrode, using an iontophoretic reference electrode in combination with either the first or second electrode. This invention can be used to control the resistance at a relatively constant level by a superimposed AC signal. In addition, this invention can adjust other iontophoretic electrical parameters, such as current level or time of administration, based on the electrical resistance measurement at the treatment site. This improved method may be used to improve the precision of iontophoretic extraction of the compound from the body tissue through the localized region, or to improve the precision of iontophoretic delivery of the compound through the localized region into the body tissue.